Anna Sumner’s craving for sleep began when she was an 18-year-old high school senior. She thought nothing of it.

When it followed her to college, she blamed it on stress. She was working so hard, she told herself, her body just needed the extra rest. But it was more than that. She would choose naps over eating lunch, working out, or being with friends. Every night after dinner, she came back to her dorm room to sleep. If her parents called on those evenings, her roommate would cover for her, telling them she had gone to the library.

After graduation, Sumner moved to Bangkok to teach English. Her sleeping continued, and so did her rationalizations. It was OK that she was napping between every class because she was adjusting to a warm climate. Then she spent a winter working in London. There, her excuse was the dark and dreary sky.

Her parents started worrying after she moved back to the U.S. for law school. The summer after her first year, she lived at their house in Mississippi while working for a law firm. “Every day I’d go to work, come home, say ‘Hi Mom and Dad’, and go to bed,” she recalls. “That was the entire summer.”

Sumner needed sleep like an addict needs a fix. “It was this overpowering desire in me, a physical urge,” she says. “And there was always the hope that, maybe this time, I would wake up feeling better.”
Sumner was almost 30 before finally confronting her problem. She had joined a high-profile law firm in Atlanta and, for the first time in her life, didn’t have a flexible schedule. She couldn’t nap without raising eyebrows. “That’s when it finally hit me,” she says. “This is not how you’re supposed to feel.”

In the fall of 2005, she sought help at the Emory Clinic Sleep Center. She learned that her problem, known as hypersomnolence, was rare but not unheard of. Over the next six years, a team of doctors there analyzed the chemicals in her brain and in the brains of 31 other hypersomniacs. They fingered one mysterious substance as the culprit.

When they tried to publish their data, many experts simply didn’t believe it. The prevailing theory is that excessive sleep stems from a failure in the brain’s arousal system, not from some unknown sleep-inducing chemical. Plus, the field had been burned decades before, when another group had trumpeted the discovery of a new, naturally occurring sleep molecule—and been proven wrong. But after being rejected at several other top-tier scientific journals, the data from the Emory researchers appeared yesterday in Science Translational Medicine.

Depending on how it is received by academia and the pharmaceutical industry, the study could lead to a new blockbuster sleeping pill, raking in billions of dollars and improving the lives of millions. Or it might fall flat.

In any case, the work gets credit for Sumner’s remarkable re-awakening.

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During one of Sumner’s first sleep tests at Emory, she was asked to take a nap in her hospital room. A noisy construction project was going on outside, so noisy that she thought it had to be part of the test. “Like, you really did have a sleep disorder if you could sleep through the jackhammer outside your window,” she says. She had no trouble dozing off.

The doctors diagnosed her with hypersomnolence, a catchall term for unexplained sleepiness that isn’t narcolepsy (that condition, by contrast, usually comes with sudden muscle weakness and a quick onset of REM sleep). The doctors prescribed a handful of stimulants—high doses of Ritalin, Provigil and amphetamines—and the medications improved her day-to-day function. But she always felt hopped up and artificial. Worse, the drugs gradually stopped working.

Sumner began having long sleeping spells like never before. She’d go to bed one night and wake up a full day later, or more—her longest stint was 53 hours. She’d open her eyes and feel completely disoriented, staring at her alarm clock with no idea whether the time was AM or PM. First it was once a month, then every two weeks, then every week. “I started approaching sleep with this trepidation,” she recalls. “Is tonight going to be the night?”

In April 2007, she took a leave of absence from her firm—a heartbreaking decision for the ambitious young woman. She spent the next year living with her parents, either at their home in Mississippi or hers in Atlanta. She couldn’t drive and was on full-time disability.

The doctors at Emory, led by neurologist David Rye, weaned Sumner off the stimulants and decided to look more closely at the chemicals bathing her brain. Rye had a hunch about what was going wrong, but his idea had a tired, tainted history.

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In the late 1980s, about a dozen people living in a rural community outside of Lucca, Italy, came down with a strange sleeping sickness, abruptly falling into a coma-like state for a half a day or more. The local press went wild with the idea of a raging sleep epidemic.

The condition, known as recurrent stupor, resembled an overdose on a benzodiazepine, such as Valium. But the sleepers swore they hadn’t taken any drugs, and blood tests backed them up. Researchers at the University of Bologna treated the sleepers with flumazenil, a drug that blocks benzodiazepine activity in the brain, and it promptly woke some of them up. So putting all of that together, the scientists proposed that the sleepers naturally carried a benzodiazepine-like drug in their brain. They named this mysterious substance ‘endozepine’ (short for endogenous benzodiazepine), and in 1998, published a paper claiming that this mystery chemical caused recurrent stupor.

Other researchers, though, weren’t convinced, and eventually rooted out the truth: The sleepers had indeed been popping benzos, whether they knew it or not. “Some of these cases boiled down to patients getting slipped the mickey at the local cantina,” Rye says.

The medical establishment was quick to pounce on the unfounded theory. In 1998, the prestigious journal The Lancet published a colorful commentary about the affair, written in the style of a classic fairytale. The last line gave the moral of the story: “At times, it seems, the gullibility of the experts surpasses that of the lay.”

Rye’s group and several others around the world had also noticed that flumazenil had positive effects on some people with hypersomnolence. But in the wake of the scandal, Rye put this line of research on hold. “People got a very bad taste in their mouths,” he says. The general feeling in the field was “we got duped on this one, and that’s not going to happen again.”

But when Anna Sumner came along, Rye’s team at Emory thought it was time to dust off the old theory. In May 2007, they gave her a spinal tap, an invasive procedure that collects cerebrospinal fluid (CSF), the clear substance that’s produced in the middle of the brain and flows down the spinal cord. CSF protects the brain mechanically, by keeping it buoyant, but it’s also chock-full of proteins and chemicals involved in brain-cell communication.

Sumner’s CSF was quantifiably abnormal. It contained a high level of a substance that, like benzodiazepines, activates the chemical messenger GABA. This neurotransmitter acts as a shutdown switch in the brain, dialing down consciousness so we can sleep. Sumner, it seemed, was carrying a bona fide endozepine.

Andy Jenkins, an anesthesiologist at Emory working on Sumner’s case, joked with her that if another woman were carrying around the same amount of GABA-activating sedative, she could practically be operated on. “That’s what I was walking around with on a daily basis,” Sumner says.

But it was good news, she knew, because it pointed to an antidote.

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Flumazenil, originally made by Roche Pharmaceuticals in Basel, Switzerland, is not a commonly used drug. The GABA blocker is typically given for benzodiazepine overdoses, and less frequently, for reversing the effects of anesthesia.

Sumner got her first dose in June 2007. The liquid dripped from a plastic bag down through a tube and into a vein in her arm. For the first time in a long time, she felt truly—naturally—awake. “It was like my eyelids opened,” she says.

But the feeling was bittersweet. Flumazenil, never meant to be a chronic drug, only came intravenously. If Sumner ever wanted to leave the hospital, she couldn’t take it with her. “I had this great hospitalization, but then I went home and went immediately back to sleep,” she says.

Sumner (a lawyer, remember) spent the next eight months working personal and professional connections to get her hands, and her brain, on flumazenil. Roche executives in Switzerland agreed to ship her the drug in its raw form. After some hassle with customs officials, the white powder eventually made it to Atlanta. Sumner has a photo of her parents in an Emory lab, grinning at a cooler full of their daughter’s miracle drug. Sumner also leapt regulatory hurdles to get a ‘compassionate use exemption’ from the FDA, allowing her to take the drug for an illness it hadn’t been approved to treat.

Finally, she found a compounding pharmacy in Atlanta to turn the powder into two forms: an under-the-tongue dissolvable pill that she pops during the day, and a slow-release cream that she smears on her skin at night.

Medication in hand, Sumner just needed one more thing before resuming a normal life: physical therapy. She had been on what amounted to bed rest for almost a year, and needed to re-learn how to use her muscles. At first, she couldn’t walk for more than five minutes without fatigue.

She went back to work in April 2008. She says her life has been great ever since—no more naps or sleeping spells, no drug side effects. “It’s just been blissful.”

✼

Meanwhile, Rye’s team was analyzing the CSF of other people with unexplained daytime sleepiness. The new study includes 32 people (including Sumner), most in their 30s and sleeping about 75 hours a week. All carry a mysterious “bioactive component” in their CSF (the researchers stopped short of using the loaded “endozepine” term). Seven found relief with intravenous treatment of flumazenil.

Most of the study revolves around the scientists’ attempts to figure out what exactly the mystery chemical is. Spoiler alert: they couldn’t quite nail it down. “It’s not like Abby on NCIS with a mass-spec machine, where you push a button and 30 minutes later you get an answer,” Rye says.

Here’s what the researchers’ experiments have discovered so far. It’s a small molecule, somewhere between 500 and 3,000 Daltons (a measure of atomic mass). It’s probably a peptide (a short chain of amino acid) because it gets chewed up in the presence of trypsin, an enzyme that eats peptides. Most importantly, the substance activates the GABA system in a specific way. GABA works by binding to a receptor, like a key in a lock, to make a brain cell quieter, less excitable. The mystery molecule, Rye says, is like WD-40, allowing GABA to interact with its receptor more smoothly.

Rye first submitted the paper to an elite medical journal in March of 2011. The reviewers weren’t thrilled, to say the least, and they all brought up the old Italian data. Rye’s team did some additional experiments, and sent the paper to another top-notch publication. Again, no dice. Then they sent it to Science Translational Medicine (which also has a stellar reputation) and, after a few more additions, it was published yesterday.

So now what do people think?

“It’s an outside-the-box kind of idea,” says Ken Solt, an assistant professor of anaesthesia at Harvard Medical School. Before this paper, he explains, most people thought all types of hypersomnolence were like narcolepsy, which is caused by a reduction of proteins in the brain’s arousal system. This is showing the converse: a new chemical that ramps up the brain’s sleep systems. The experiments were well controlled and particularly impressive because CSF (requiring a spinal tap) is difficult to collect. “It’s pretty convincing,” he says.

“This is a fascinating study,” notes Nick Franks, a professor of biophysics and anaesthetics at Imperial College London. The same GABA-enhancing mechanism, he adds, is behind the action of most anesthetics. But he also wonders, is the unknown substance the cause of the sleep disorder, or simply a consequence of living with it?

Rye says that with more time, resources, and expertise, other groups should be able to isolate the compound. And why wouldn’t they try? “If I know this molecule, I actually know the target of things that could put you to sleep, and things that could wake you up,” Rye says.

The financial incentive is potentially enormous: Provigil, a drug that helps wake people up and is often used as a ‘cognitive enhancer’ to promote concentration, had $1.1 billion in sales last year. The popular sleep aid Ambien made nearly $2 billion a year before going off patent in 2005. Identifying the mystery sleep molecule “would have a huge market in the West,” says Pietro Cortelli, a professor at the University of Bologna. (Cortelli has had patients similar to Sumner over the years, and has always believed in the possibility of an endozepine. But he was not part of the Italian research group whose patients turned out to be secretly drugged.)

But there are many reasons why Big Pharma might not bite. If the substance turns out to be on the larger side, then turning it into a drug would be problematic because it would have trouble crossing the blood-brain barrier, the sheet of cells that protects the brain from the blood supply. Then there are business issues. Roche, for example, knows all about the Emory research from helping Sumner get her flumazenil. But company execs told Rye they didn’t think there was enough market potential.

And maybe they’re right. Sleep aids that target GABA are already out there. And some experts say that the market for sleep aids is far less attractive now that there’s a cheap, generic form of Ambien.

Without private investment, though, it’s unclear what will happen to Sumner and the others who have this rare sleeping disorder. Anna’s flumazenil stash from Roche will run out in about a year. And the company has no interest in making any more because it’s now a generic drug. Several companies make it here in the U.S., but in small quantities because the number of people getting it for drug overdoses is so few.

Sumner hopes that her story will show how critical sleep is to our everyday existence. “If you don’t get enough you can literally die, and if you sleep too much you have nothing left,” she says. And to the millions of people who suffer from some kind of sleep trouble, she adds, take heart in the sure-and-steady progress of science. “If nothing else, I want people to know that there is hope.”

*

Update: I made a big oversight in not mentioning the efforts of one of Rye’s colleagues, Kathy Parker, who was the first person to suggest that they dust off the old endozepine idea. She was also involved in helping Sumner get flumazenil from Roche.

There are 42 Comments. Add Yours.

Wow. I wonder what the trigger was to produce the endozepine in Anne at around age 18.

Virginia Hughes
November 22, 2012

Isn’t that fascinating? I asked Rye and he said that no one has any idea.

Ann Finkbeiner
November 22, 2012

And why didn’t the Italian villagers test positive for drugs if they’d been drugged? This is just a fascinating story.

Ed Yong
November 22, 2012

Ginny, this is just such an unfeasibly good piece.

Virginia Hughes
November 22, 2012

@Ann: not totally sure about this, but I think that it’s a combination of: 1) chemicals may linger in the brain after they’re not detectable in blood, and 2) blood tests can be wrong.

@Ed: thank you, sincerely. Aren’t you supposed to be away from the Internet today?

Chad Jones
November 22, 2012

Great article! I can’t imagine going to bed every night not knowing if I was about to sleep for 50 hours.

David Rye
November 22, 2012

This is Dr. Rye. Ginny – awesome article. You nailed it! As to surreptitious lorazepam in the Italian’s urine – it and its metabolites elude detection by routine tox screens at the time (most are still pretty poor). We therefore had to spend a nice penny (actually nearly $6,000) to have our patient samples of urine and blood tested by a forsensic laboratory with ultra-sensitive methods – many in duplicate!
david

Virginia Hughes
November 22, 2012

Thanks for the insight, David!

Ann Finkbeiner
November 22, 2012

@Dr. Rye: Wow. I’m going to take up mickey-slipping. And how wonderful to hear straight from the source. So thank you.

George Johnson
November 22, 2012

What an interesting and original story. Congratulations.

Virginia Hughes
November 23, 2012

Thank you, George!

TBrown
November 22, 2012

I’ve been diagnosed with idiopathic hyper-somnolence and it started when I was 18 as well. I’m 25 now and have been seeing specialist after specialist with every test coming back normal. This article at least gives me some hope that there are others out there with this wacky condition and *someone* is looking into it. Currently running the amphetamine circuit but have had nothing but bad reactions to them so far.

Virginia Hughes
November 23, 2012

Best wishes to you, TBrown — hope things improve, and soon.

Elspeth
November 23, 2012

I got a diagnosis of Idiopathic Hypersomnia last year, after about 4 years of 16-20hrs of sleep a day. and symptoms extending back into my mid-teens.

I’m on Provigil, but it’s not enough for me to actually work, or live a normal life.

Hearing that there’s hope of tracking down a cause, of maybe finding a medication that actually works – I cried. Even if it’s years away, knowing that one day I might again be able to leave the house every day without fearing I was going to pass out and not make it home safely – that’s more hope than I’ve had in a long time.

Elle
November 23, 2012

For years I have written off my excessive sleeping bouts to depression and fibromyalgia and don’t go into lengths about it with my doctors thinking they will do the same. I say I was sick for a few days, not that I slept for 3 days. There s both shame and feelings of guilt.

Like Anna, I fear going to sleep because I don’t know if I will wake up the next morning or not for days,

It’s time for me to move pass the fear and self judgement and be honest with my doctors. It can very well be caused by my depression or could be something else.

Thanks for presenting Anna’s story and Dr. Rye’s work.

Alice Jones
November 24, 2012

Just wondering if this disorder is related at all to Chronic Fatigue Syndrome?

Jade Clarke
November 24, 2012

What an excellently written article! Its an interesting subject but could have so easily been overloaded with too much science. Great Work!

Valerie Van Etten
November 24, 2012

I’ve struggled withe Restless Leg Syndrome for 40 years before I found a support group that finally validated what I had been experiencing. Then, in 1994 I started sleeping for days at a time and now I would rather sleep than do almost anything.
My lack of interest in life led me to think that I was depressed and the sleep was a retreat. Could this be physiological instead? I describe my sleep patterns as sleeping all the time or not being able to sleep because of the RLS. To make matters worse, I also suffer from FSH Muscular Dystrophy. Advice?

Krishna
November 24, 2012

Great article. Wonderful success story of academic translational research. But I was wondering about the exact concerns from reviewers from the journals the article had been sent to previously? Sorry, I haven’t gotten around to reading the full article so I am not sure if the work published is comprehensive.

Laura
November 24, 2012

I am beginning to suspect I also suffer from this condition. I’ve been diagnosed with depression dating back at least 10 years, but over the last few years I have been sleeping more and more. Lately it has been really bad. Every night I sleep 12-15 hours, and can’t wake myself up before then. I’m going in for a sleep study next week. If flumazenil was licensed for this in the UK, it would change my life. There’s so much I want to do, but at the moment I’m missing everything because I sleep all the time. The added guilt and shame makes it doubly miserable.

Michael
November 24, 2012

What an incredible story. And putting a complicated scientific problem into a readable story deserves kudos. And throwing in an Abby (from NCIS) reference made my day.

I’m glad I decided to read the comments, because a couple of my questions were answered by you and Dr. Rye.

My one nitpick would be whether Big Pharma would be interested in the biochemical. If the mystery molecule had some advantage over current sleep drugs like Ambien (such as quicker sleep and less grogginess when waking up), or it had a positive effect in jet lag (for example), then it could be a multi-billion dollar blockbuster. As someone who spent most of his career in medical R&D, I’ve seen lots of interesting developments like this one.

Thanks again.

Maria
November 25, 2012

What about those of us that can not sleep and the only solution is benzos, why can no one find a safe cure for those of us that can not sleep.

Kyle Simonson
November 25, 2012

I’ve avoided looking into my seemingly innate desire and ability to sleep 24 to 36 hours. Any day of the week, any time. Catnaps, closing my eyes sitting up, and falling fast asleep. I’m fortunate to have an understanding employer, but that might not always be the case. I should probably look into this while I have health insurance.

Thank you for the fantastic article. You are a superb writer.

samcar1
November 25, 2012

Narcoleptic here, 25+ years, REM onset < 2 mins, sometimes I can blink and I dream, legit, documented. no cataplexy. chronic compulsion to sleep. Nuvigil okay for a few hours, nervous to introduce an afternoon fix of methylphenidate or similar. any studies in the works that need my "type"?

Brad Dawkins
November 26, 2012

Dr. Rye: Perhaps, if isolated and characterized properly, this mystery chemical could be useful in the arena of chemically-induced comas.

I am also wondering if this chemical may be related to hibernation. Although humans don’t hibernate, such physiologic hyper somnelence is evolutionarily very old. We probably still retain some of the biological underpinnings for it. Does a person under the influence of this chemical exhibit the physiologic characteristics seen in higher animals during hibernation?

There may even be a role for such a chemical in long-duration space missions.

Berta
November 26, 2012

Fascinating article. I hopeSumner will be able to continue getting the medicine that’s been helping her.

David Rye
November 26, 2012

Brad—interesting thoughts—not hardly once did I contemplate what you bring up. There is nothing obvious that suggests a hibernating state per se (vis a vis temperature or autonomic measures). That being said, these folks do have some complaints suggesting a dys-autonomia which we might presume reflects effects of GABA either peripherally or on central/brain autonomic circuits–not only in our experience but that of others. Will need to ponder this a bit more

CJS
November 26, 2012

This is shockingly well-written. Great job!

m
November 27, 2012

Fascinating..! I’ve had hypersomnia since I was in my teens. At my peak, I was sleeping about 16-18 hours a day. With stimulants, I’ve whittled that down to 8-10, although sometimes I still need more.

At least in my family, there seems to be a strong genetic component. On my mom’s side, everyone is a caffeine junkie (or worse), and we’re all hypersensitive to drugs that might induce sleep. If you give me dramamine, for example, I’ll be knocked out for at least twelve hours, whether or not that was the intent. Strangely, I’d never thought of it as a real disorder – more like an addiction that I counteract with drugs. Adderall has worked well for me, but only if used irregularly. It’s nice to know that there might be another path, rather than uppers. Do they know anything yet about the side effects?

Cathy
November 29, 2012

Interesting. Our son suffered a head on collision 14 years ago. It led to an atypical circadian rythum sleep disorder where he can sleep 24 hours, or 5 – 12 hours. It takes about 3 hours to go from awake to being able to move muscles and get up. A doctor said it is like he was blind but all efforts to regulate sleep with medafonil, melatonin and attemps to pattern led to more fatigue, and anxiety. The best help is to let his body tell him when to go to bed with medafonil at times to lighten fatigue when it is severe.
This has been most debilitaing because he cannot manage a job when he cannot get to work regularly or in daylight hours. His day and night are most often long non regular circles f not 12/12 hours but a slow non regular rythum say 5 – 20 hours of his day to 5 – 24 hours for night. His body will not wake him until it says to wake.
Perhaps this finding will offer him help?

Nancy A
November 30, 2012

Dr Rye, Congratulations on your findings and well-received research. I was invited to participate in your study, but felt I was stable in terms of medications at the time and was nervous to go off them. I wanted to ask you if any of your research patients have ever had to take a benzodiazepine for any reason and was their reaction to it different from someone without the disorder? Also, have your research patients undergone MSLTs and do they enter REM quickly like Narcoleptics?

Kelly
December 1, 2012

What is the best way for those of us with similar situations to try to get help? Even if the treatment isn’t available, the peace of mind from removing “idiopathic” from the diagnosis would be tremendously beneficial.

Virginia Hughes
December 1, 2012

Hi Kelly,

I’m probably not a good person to be giving advice, as I don’t know much about the clinical side of things. But I would think that if you went to a large, academic medical center (meaning a hospital that does research and is affiliated with a university) and went specifically to its sleep center, that the doctors there could at least point you in the right direction.

Megan
December 30, 2012

I am a 44 year old woman and have been diagnosed with everything from Chronic Fatigue Syndrome to Crohns Disease to hypothyroidism and taken antidepressants, amphetamines and anything else, with only minimal affects. I am emailing this to my doctor. THANK YOU!!!

Lloyd
March 2, 2014

Several people have asked what to do for themselves or their loved ones who are having a similar experience. I highly recommend the Hypersomnia Foundation as a good place to start for information about getting access to better treatment: http://www.hypersomniafoundation.org

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